tbuckley/cabot-search huggingface dataset:
CSIG-08. GAIN-OF-FUNCTION MUTANT P53 REGULATES LONG-NONCODING RNAS TO CONTROL HIF1Α TRANSCRIPTION IN GLIOBLASTOMA
Authors: Ying Zhang, Ying Yuan, Cassandra Grello, Brian Reon, Myron Gibert, Collin Dube, Yanzhi Yang, Kadie Hudson, Benjamin Kefas, Anindya Dutta, Roger Abounader
Journal: Neuro-Oncology (2023)

Abstract P53 is mutated in a large subset of glioblastoma (GBM). Most hot-spot p53 mutants are gain-of-function (with only partially understood mechanisms). To investigate the role of gain-of-function mutant p53 (GOF-Mut-p53), we performed ChIP-seq analysis of GOF-Mut-p53 R273H, the most common p53 mutation in GBM. We identified and verified numerous GOF-Mut-p53 targets that differed from those of wildtype p53. Among the 2,830 targets of GOF-Mut-p53 were 535 long non-coding RNAs (lncRNAs), the majority of which we also found enriched in Mut-p53 human tumors and deregulated in the TCGA database. LncRNAs play important regulatory roles in cancer. One of the most highly enriched lncRNAs was LINC00643. We first performed ChIP confirmation of GOF-Mut-p53 binding to the promoter of LINC00643. We then showed that GOF-Mut-p53 inhibits LINC00643 expression. Furthermore, we found that LINC00643 is deregulated in human GBM and LGG and correlated with patient survival. Overexpression of LINC00643 led to a significant inhibition of GBM cell proliferation, migration, invasion and in vivo xenograft growth. Co-expression of human LINC00643 or its mouse homologue with PDGF and Cre in RCAS transgenic mice (N/tv-a; Ink4a-arf-/-; Pten-fl/fl) reduced tumor growth and improved animal survival. These data show that GOF-Mut-p53 exerts oncogenic effects in GBM by downregulating LINC00643. To elucidate the mechanisms of action of LINC00643, we performed Chromatin Isolation by RNA purification high-throughput sequencing (CHIRP-seq) to identify its binding targets. We found that LINC00643 binds to the HIF1α enhancer region. Overexpression of LINC00643 and knockdown of GOF-Mut-p53 in GBM cells under hypoxia growth conditions reduced HIF1α mRNA and protein expression. LINC00643 also regulated the expression of numerous hypoxia-regulating genes downstream of HIF1α. Our study shows for the first time that GOF-Mut-p53 transcriptionally regulates a subset of lncRNAs and that GOF-Mut-p53-regulated LINC00643 regulates hypoxia in GBM.
DISP-06. EXAMINING THE INFLUENCE OF NEUROSURGICAL ONCOLOGY PROVIDER ACCESS ON DIFFUSE GLIOMA SURVIVAL OUTCOMES: A NATIONWIDE COUNTY-LEVEL APPROACH
Authors: Youssef Sibih, Sudheesha Perera, Anthony DiGiorgio, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2023)

Abstract Neuro-oncology as a field has markedly improved understanding of the molecular underpinnings of brain cancer, yet fundamental concepts driving patient outcomes such as access to neuro-oncology subspecialty care remain poorly understood. The aim of this study was to determine the density of neuro-oncologist in the US and correlate disease-specific mortality with provider density. The data was calculated from two national data registries: Centers for Medicare &amp; Medicaid Services (CMS) and Surveillance, Epidemiology, and End RESULTS: (SEER) database. Linear regression modeled three primary outcomes of interest: neurosurgical oncologist per capita, average distance to subspecialist care, and incidence-based mortality of diffuse glioma. Neurosurgical oncologists were classified as providers who billed for CPT code “61510” with at least 10 total services per year over the 5-year duration. In the US, a total of 113 catchment areas were constructed. Mean number of subspecialty providers per capita was 1.80 and the average distance traveled to the nearest provider across the US was 49.9 miles (range 5–151 mi). The mean age-adjusted incidence-based mortality rate among all catchment areas represented was 5.42 deaths per 1000 person-years. Catchment areas with a higher average income were associated with a greater number of subspecialty providers (95% CI 2.13 to 3.44, p &amp;lt; 0.027). Among all US regions, there was no correlation between mortality and provider density or average distance to care. However, Hispanic ethnicity displayed highest incidence-based mortality (r = 0.601, 95% CI -5.02 to -0.944, p &amp;lt; 0.0051). US regions associated with higher poverty and lower average income were associated with greatest mortality (r = 0.45, p &amp;lt; 0.0058). This population study illustrates differences in provider density throughout the United States. Additional research is needed to devise strategies that ensure equitable geographic access in order to optimize patient care and reduce disease burden.
EPCO-15. DETECTING HISTOLOGIC &amp; CLINICAL GLIOBLASTOMA PATTERNS OF PROGNOSTIC RELEVANCE
Authors: Bhakti Baheti, Sunny Rai, Shubham Innani, Garv Mehdiratta, Sharath Chandra Guntuku, MacLean P Nasrallah, Spyridon Bakas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma is the most common adult primary brain tumor. Limited improvement in patient prospects over the last 20 years reflects our limited disease understanding. Robust prognostic patient stratification from whole slide images (WSI) &amp; clinical data using interpretable computational methods could improve disease understanding and patient management. MATERIAL AND METHODS The TCGA-GBM and TCGA-LGG data collections were reclassified according to the 2021 WHO classification criteria, identifying 188 glioblastoma (IDH-wt, Gr.4) cases and stratifying them to short- (&amp;lt; 9 months) and long-survivors ( &amp;gt; 13 months). H&amp;E-stained WSI were comprehensively curated to remove artifactual content. An interpretability mechanism based on weakly-supervised attention-based multiple-instance-learning was employed. The prognostic relevance of associated clinical data was also evaluated both independently and integratively, using XGBoost and ‘SHapely Additive exPlanations’. Late fusion amalgamates the advantage of WSI patterns with clinical features by averaging the output probabilities of two distinct models at the decision level. Quantitative performance evaluation was based on a 10-fold monte carlo cross-validation, with training (80%), validation (10%), and test (10%) sets. RESULTS Our imaging, clinical, and integrative multi-modal models revealed AUCTest of 0.68/0.72/0.75 respectively. The imaging analysis revealed correctly predicted long-survivors associated with histologically malignant areas, including necrosis, hypercellularity, atypia, infiltration, and proliferation. Correctly classified short survivors highlighted influence by aggressive infiltrative features, including leptomeningeal involvement. The clinical analysis revealed age, mutation count, and TERT promoter status as the top three features contributing to stratification, in the XGBoost model. CONCLUSION Our findings support data-driven histology &amp; data interpretation of algorithmic decisions contribute to further understanding of glioblastoma by identifying morphology patterns &amp; clinical patterns of prognostic relevance. Integration of multiple modalities can be a powerful approach for improving the performance of AI models.
BIOM-49. FGFR ALTERATIONS IN GLIOMAS; CLINICAL, RADIOGRAPHIC AND MOLECULAR CHARACTERIZATION
Authors: Colin Hill, Antonio Iavarone, Dalissa Tajera, Macarena de la Fuente
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND FGFR-TACC is the most prevalent type of gene fusion in adult gliomas. It is present in 3-6% of IDH WT (wild-type) gliomas. Due to their histopathological and molecular features, it has been suggested that FGFR3-TACC3 fusions (F3T3) gliomas represent a unique entity among IDH WT gliomas. F3T3 are potent oncogenes that confer sensitivity to FGFR inhibitors. Preliminary data showed promising results of these alterations as actionable targets by FGFR inhibitors. METHODS We retrospectively analyzed molecular data on 912 glioma patients treated at our institution from 2014 to 2023. RESULTS We identified 22 gliomas (2.5%) with FGFR alterations. Median age was 60 years, 14 were female. 14 patients (64%) self-identified as Hispanic. 18 had a diagnosis of glioblastoma, 3 had other gliomas, and one had a low-grade neuroepithelial neoplasm. Ten patients had tumor location in the temporal lobe, 6 frontal, 5 parietal, 3 occipital, 1 multifocal, and 1 basal ganglia. 19 patients had enhancing tumors, while three were non-enhancing. The most common FGFR alteration was FGFR3-TACC3 fusion in 14/22 patients, 6 had FGFR mutations (either single base or amino acid substitutions), one had FGFR-LMNB2 fusion, and one had FGFR3 amplification. 86.4% of our patient cohort (19/22) had a confirmed TERT promoter mutation, while 100% of GBM patients with known TERT promoter status had an associated TERT promoter mutation. 10/22 had CDKN2A/B alterations. One patient had pathology-proven systemic metastases. CONCLUSIONS FGFR3-TACC3 fusions (F3T3) gliomas represent a unique entity among IDH WT gliomas. In our cohort, 100% of the patients with F3T3-positive glioblastomas also had an associated TERT promoter mutation. To our knowledge, this is one of the larger cohorts showing the association between FGFR3 and TERT promoter alterations in glioblastomas. RESULTS will be validated through the upcoming clinical trial ETCTN 10559, including tumor evolution and mechanisms of resistance.
EPCO-35. IDENTIFICATION OF DIVERSE IMMUNE PHENOTYPES IN NF-1 GLIOMA BY SINGLE NUCLEI GENE EXPRESSION ANALYSIS
Authors: Luciano Garofano, Young Taek Oh, Ryan D Najac, Michele Ceccarelli, Marc Sanson, Anna Lasorella, Antonio Iavarone
Journal: Neuro-Oncology (2023)

Abstract Neurofibromatosis type 1 (NF-1) is the most common cancer predisposition syndrome in which 15-20% of affected individuals develop glioma. Large scale DNA and RNA bulk profiling showed the high molecular complexity of NF-1 glioma with the tumor cellular ecosystem constituted by multiple malignant clones and heterogenous immune microenvironment. However, the composition and function of infiltrating cells was mostly hidden in the bulk tumor mass, and the extended granularity of NF-1 glioma immune microenvironment remained still unexplored. Here, to address this challenge, we collected glioma samples from 53 NF-1 patients including 27 high-grade and 26 low-grade tumors, and we analyzed their gene expression at the highest resolution through single nuclei RNA sequencing. A total of 288,372 single cells have been classified by integrating multiple computational approaches (including genomic copy number inference, gene signature enrichment, pathway-based deconvolution and integrative non-negative matrix factorization). The non-tumor cell compartment (124,082 cells, 43%) has been dissected for the deep characterization of each cell type that populate the microenvironment of NF-1 glioma. We unraveled the complexity of the immune infiltration and identified different subpopulations exhibiting specific immune functions within myeloid and lymphoid components. Different glioma niches have been revealed by comparing the relative composition of the immune microenvironment across the tumors. Recruitment and activation of cytotoxic CD8+ T cells and natural killers by an active crosstalk with dendritic and pro-inflammatory myeloid cells defined an immune-supportive phenotype that can mediate a potential anti-tumor response in low-grade NF-1 glioma. Regulatory T cell infiltration and effector T cell exhaustion, instead, induced immune suppression in another tumor niche. Conversely, the complete absence of lymphocytes characterized a large set of cold tumors, mostly high-grade glioma. The elucidation of the complex immune interplay in the different tumor niches provides novel insights for the application of immunotherapies in NF-1 glioma patients.
CTIM-09. PHASE 1/1B TRIAL OF FC-ENGINEERED ANTI-CD40 AGONIST MONOCLONAL ANTIBODY (2141-V11) INFUSED WITH D2C7-IT IN ENHANCING DISEASE BY CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMA (RMG)
Authors: Annick Desjardins, Vidya Chandramohan, Daniel Landi, Katherine Peters, Margaret O Johnson, Justin Low, Mustafa Khasraw, Stevie Threatt, Chevelle Bullock, James Herndon, Eric Lipp, Allan Friedman, Henry Friedman, David Ashley, Juan Osorio, Jeffrey Ravetch, Darell Bigner
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND D2C7-IT is a dual-specific immunotoxin. Recombinant antibody fragments bind the wild-type epidermal growth factor receptor (EGFRwt) and its mutant EGFR variant III (EGFRvIII), triggering internalization and intracellular delivery of the Pseudomonas exotoxin, D2C7-IT cell-killing component. Single intratumoral delivery of D2C7-IT in animals generates an antitumor response by directly killing tumor cells and indirectly activating an adaptive T-cell response. However, tumor-associated macrophages (TAMs)-mediated immunosuppression limits its efficacy. Eliminating MG immunosuppression via CD40 co-stimulation enhances D2C7-IT-induced antitumor responses by activating a TAMs proinflammatory phenotype and promoting long-term tumor-specific CD8+ T-cell immunity. We initiated a phase 1 trial of D2C7-IT+2141-V11 (Fc-engineered anti-CD40 agonist) administered via CED in rMG patients. METHODS Eligibility includes adult patients with solitary supratentorial rMG (WHO grade 3/4); ≥ 4weeks after chemotherapy, bevacizumab, or investigational agent; adequate organ function; and KPS ≥70%. Cohorts of 3 patients were treated with increasing doses of 2141-V11 to determine the recommended phase 2 dose (RP2D) when administered sequentially following D2C7-IT (166,075ng) via CED. Five dose levels (DLs) were evaluated (2141-V11 at: DL1: 0.70mg; DL2: 2.0mg; DL2**: 3.0mg; DL2*: 4.0mg; DL3: 7.0mg). RESULTS As of June 5, 2023, 27 patients had been treated (3 patients on DL1 and DL2; 2 on DL3 and DL2*; 17 on DL2**). No dose-limiting toxicities were observed; however, lower DLs were added due to higher frequency of adverse events (AEs) expected with D2C7-IT+2141-V11 within DL3 and DL2* (fever, neurologic symptoms). 13/27 patients remain alive (range 4-22months after therapy). No grade 4 or 5 AEs related to D2C7-IT+2141-V11 were observed, while grade 3 related AEs include one each of: dysphasia, encephalopathy, headache, hydrocephalus, paresthesia, and pyramidal tract disorder. CONCLUSIONS The RP2D for intratumoral infusion of D2C7-IT+2141-V11 via CED is identified. The protocol was amended to evaluate the addition of cervical perilymphatic injections of 2141-V11 post CED of D2C7-IT+2141-V11.
CTNI-09. DOSE ESCALATION FOR NEOADJUVANT STEREOTACTIC RADIOSURGERY FOR LARGE BRAIN METASTASES: PHASE I RESULTS
Authors: Erin Murphy, Kailin Yang, John Suh, Jennifer Yu, Glen Stevens, Lilyana Angelov, Michael A Vogelbaum, Gene Barnett, Manmeet Ahluwalia, Gennady Neyman, Alireza Mohammadi, Samuel Chao
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Surgical resection may be required for large and symptomatic brain metastases. Adjuvant radiotherapy or stereotactic radiosurgery (SRS) is needed to reduce local recurrence. Adjuvant radiosurgery has been associated with higher rates of leptomeningeal failure and radionecrosis. We conducted a phase I trial for brain metastases greater than 2 cm in size to determine the safety of preoperative SRS at escalating doses. METHODS Radiosurgery dose was escalated at 3 Gy increments starting with RTOG 90-05 dosing for 3 cohorts based on maximum tumor diameter: 18 Gy for &amp;gt;2-3 cm, 15 Gy for &amp;gt;3-4 cm, and 12 Gy &amp;gt;4-6 cm. Dose limiting toxicity (DLT) was defined as grade III or greater acute toxicity. Patients underwent surgical resection within 2 weeks and were followed with imaging and physical evaluations every 3 months. RESULTS For tumor size &amp;gt;2-3 cm, patients were enrolled up to the second dose level (21 Gy); for &amp;gt;3-4 cm and &amp;gt;4-6 cm cohorts the third dose level (21 Gy and 18 Gy, respectively) was reached. 35 patients were enrolled with 36 brain metastases treated with preoperative radiosurgery. There were 2 DLT (wound issues) in the &amp;gt;3-4 cm arm at the third dose level and 1 DLT (hemorrhage) in the &amp;gt;4-6 cm arm at the third dose level. The maximal tolerated SRS dose (MTD) for &amp;gt;-2-3 cm arm was not reached, for &amp;gt;3-4 cm arm was 18 Gy and for &amp;gt;4-6 cm arm was 18 Gy. With a median follow-up of 64 months, the 6- and 12-month local control rates were 88.8% and 79.1%, respectively. The 2-year rate of LMD was 0%. CONCLUSION This Phase I preoperative SRS dose escalation trial found a MTD for brain metastases greater than 3 and up to 6 cm in size. The phase II trial will be conducted at the maximum tolerated SRS doses.
CTNI-20. NIMOTUZUMAB COMBINED WITH CONCURRENT CHEMORADIOTHERAPY IN THE TREATMENT OF NEWLY DIAGNOSED PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Xiaoguang Qiu, Mawei Jiang, Chao Liu, Gang Wang, Rongjie Tao, Jiankun Xu, Liangfang Shen, Yanwei Liu, Heling Wang, Chuanying Zhu, Hui Zhang, Gao Zeng, Jidong Hong, Baoshi Chen, Shujun Wang, Wenlan Bao, Jia Yang, Qingtang Lin, Huan Li, Shuai Liu, Wei Zhang, Shuxian Chen, Yongrui Zhao, Jianbing Tang, Zhen Kou, Jun Su, Peng Sun, Longyun Wang, Xiaoyang Sun, Yan Ju, Wenbin Ma, Yu Wang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Newly diagnosed pediatric DIPG is a fetal disease with a poor prognosis and lacks of effective treatments. Multiple studies have demonstrated that the median survival time for patients is less than one year. A single-armed, prospective, multicenter study was conducted to evaluate the efficacy and safety of adding nimotuzumab to concurrent chemoradiotherapy for the treatment of newly diagnosed pediatric DIPG. METHODS Patients were 3-15 years old, histologically or imaging confirmed newly diagnosed DIPG, Lansky score ≥ 60, and at least one measurable lesion. Totally 48 patients were enrolled. Nimotuzumab (150mg/m2/w) concurrent chemoradiotherapy (Temozolomide: 75mg/m2 per day. Radiotherapy: 54Gy/30f) were administered for 6 weeks following a maintenance treatment (Nimotuzumab: 150mg/m2 biweekly. Temozolomide: 150-200mg/m2 per day for 5 days every 28 day). The primary endpoint was ORR, with secondary endpoints including 1-year OS rate, PFS and safety. RESULTS Between Apr 3, 2021 and Apr 13, 2023, a total of 48 patients were enrolled with a median age of 7 years old, in which 20 patients radiologically diagnosed DIPG, 28 patients histopathologically confirmed DIPG with 25 (89.3%) had H3K27M mutation. The median follow-up was 15.2 months. The ORR was 31.3% (95%CI, 18.66%-46.25%), mOS was 10.35 months, 1-year OS rate was 27.4% (95%CI, 14.73%-41.73%), mPFS was 6.93 months, and 1-year PFS was 9.5% (95%CI, 2.46%-22.56%). Eight patients (16.7%) experienced grade 3 or above ADRs. The most common toxicities were neutropenia (40%), leukopenia (25.0%), thrombocytopenia (25.0%). anemia (5.0%), flank pain (5.0%). CONCLUSIONS Nimotuzumab combined with concurrent chemoradiotherapy showed survival benifit for newly diagnosed pediatric DIPG patients with tolerable toxicity.
NIMG-89. CNS-ISOLATED RICHTER’S TRANSFORMATION: THE FALLIBILITY OF NEURO-IMAGING AND THE CRITICAL ROLE OF BRAIN BIOPSY IN A CHALLENGING DIAGNOSIS
Authors: Sean Lee, Audriana Hurbon, Ahmed Aboul-Nasr, Dory Arevalo Salazar, Chelby Wakefield, Ritika Halder, Ravitharan Krishnadasan
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION An 81-year-old male was admitted for acute encephalopathy and failure to thrive. Workup revealed a lymphocyte-predominant leukocytosis, prominent axillary and mediastinal lymphadenopathy on CT, and multiple supra-tentorial FLAIR-hyperintense lesions that were homogenously contrast-enhancing. Axillary lymph node biopsy demonstrated small lymphocytic lymphoma (SLL), a variant of CLL. Despite concern for CNS malignancy, brain biopsy was initially deferred since the patient’s brain lesions were attributed to SLL metastasis. However on hospital day 15, he developed partial seizures, prompting stereotactic biopsy which revealed DLBCL. DATA/DISCUSSION Our case highlights the pitfalls of relying solely upon neuro-imaging to diagnose Richter’s transformation (RT) isolated to the CNS. First, MRI does not differentiate CNS metastasis of systemic lymphoma from CNS RT. A review of 35 biopsy or LP-proven cases of CNS-isolated RT showed imaging characteristics consistent with primary and metastatic CNS lymphoma. When parenchymal lesions are present, all are T2/FLAIR hyper-intense; 60% are unifocal (40% multifocal); and 95% homogenously enhance. Second, CNS-isolated RT is at least 3 times rarer than CNS metastases of CLL. Among patients with CLL, ~1% will eventually exhibit CNS metastasis but &amp;lt; 0.3% will develop CNS-isolated RT. In patients with known CLL and no evidence of high-grade transformation, it is reasonable to attribute brain lesions to CNS metastasis of CLL as opposed to RT, absent a definitive tissue diagnosis. CONCLUSION These data emphasize the importance of biopsy in the workup of CNS lymphoma, especially since treatment differs based on histopathological subtype. Given its chronic indolent course, SLL is typically managed expectantly, whereas the aggressive nature of DLBCL warrants more intensive chemotherapy. Our case also shows that in patients with suspicious CNS lesions, presence of systemic malignancy does not eliminate the need for brain biopsy, and that clinical deterioration should prompt biopsy if not already performed.
DDDR-20. FOSL1 INDUCES TMZ-CHEMORESISTANCE IN GLIOBLASTOMA VIA REGULATION OF IL-6-STAT3TYR705PATHWAY-MEDIATED STEMNESS
Authors: Jeongmin Sim, JeongMan Park, Yu Jin Kim, Dongkil Kim, Kyunggi Cho, Ju Hyung Moon, Kyoung Su Sung, Jaejoon Lim
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most lethal brain tumors with intensive resistance to drug. Although glioblastoma has been tried to treat with diverse strategies, drug resistance is still concerning. Finding new therapeutic targets to improve conventional drug sensitivity has remained a major challenge. Here, a novel therapeutic target, FOSL1, to conventional drug resistant patients was established, in which FOSL1 knockdown restores the temozolomide (TMZ) sensitivity via regulation of IL-6-induced stemness characteristic in glioblastoma cells. We show that FOSL1, contributing to poor prognosis of GBM patients, is closely linked chemo-resistant molecular signatures. In glioblastoma cells, FOSL1 knockdown is affect to apoptosis, G0/G1 arrest, tumor migration and expression of stemness hallmark. These alterations were induced by FOSL1-mediated IL-6-pSTAT3Tyr705 activation via MGMT independent manner. Finally, we show that vemurafenib, targeting FOSL1 expression, can be potential therapeutics for TMZ resistant glioblastoma. Taken together, our results demonstrate that FOSL1 facilitates TMZ chemoresistance via regulating IL-6-pSTAT3Tyr705-mediated stemness in GBM cells. FOSL1 can represent a novel therapeutic target to overcome GBM chemoresistance.